UICC Staging after Neoadjuvant/Perioperative Chemotherapy Reveals No Significant Survival Differences Compared to Primary Surgery for Locally Advanced Gastric Cancer

Round 1

Reviewer 1 Report

A very interesting and very helpful work

Author Response

We kindly thank the reviewer for the  very positive rating.

Reviewer 2 Report

This is a well-organized study with detailed univariate and multivariate analyses.

However, there are still some major concerns that required major revisions.

1.      In the results, Page 4, Line 154-155, the abbreviations of five-year survival rate (5YSR) and the ten-year survival rate (10YSR) are inconsistent with “FYSR/TYSR” in Line 157. Please check “5YSR/10YSR” or “FYSR/TYSR” in this manuscript.

Also, Page 5, Line 203 and Line 206, please check “5YSR/10YSR” or “FYSR/TYSR”.

2. Please check “Kaplan-Meier” with a hyphen in this manuscript.

3. In the Page 4, Line 176-181, this paragraph (The following variables……. All factors were included in the multivariable model without selection) could be stated in the “Materials and Methods”

4. In the left column of Tab1e 3, the “UNIVARIABLEE (ALL)” should be corrected as
“UNIVARIABLE (ALL)”.

5. In the Table 2 Baselines after PSM, the “Age” between Surgery only (66.3 +/- 11.9) and CTX + Surgery is still significantly different after PSM. Please further discuss the impact of “Age” in this study in the “Discussion.”

For the variable “Age” in the Table 1, 2, 3 and 4, the unit “years” for Age is still required.

6. In the Page 20, Line 265, there is a redundant full stop/period.

In the Page 20, Line 267, please check the term “Histoapthologic” or “Histopthologic”.

7.Although the authors noticed the limitations including different treatment strategies in this study, the impact of “adjuvant therapy” on survival of the “primary surgery” group is not clear explained in this manuscript.

Moreover, there are still some patients receiving primary surgery with advanced disease including T4a, T4b, pN3a, pN3b, and UICC IIIC.

Most importantly, adjuvant therapy may affect the survival of patients receiving primary surgery with advanced disease as above mentioned.

Please clarify and discuss whether “adjuvant therapy” is applied to “primary surgery” or not in this retrospective study. If yes, please define the indication of adjuvant therapy after primary surgery.

Author Response

1. In the results, Page 4, Line 154-155, the abbreviations of five-year survival rate (5YSR) and the ten-year survival rate (10YSR) are inconsistentwith “FYSR/TYSR” in Line 157. Please check “5YSR/10YSR” or “FYSR/TYSR” in this manuscript.Also, Page 5, Line 203 and Line 206, please check “5YSR/10YSR” or “FYSR/TYSR” 

   Reply: The abbreviations were checked and corrected

2. 2. Please check “Kaplan-Meier” with a hyphen in this manuscript

   Reply: „Kaplan-Meier“ was checked and corrected.

3. In the Page 4, Line 176-181, this paragraph (The following variables……. All factors were included in the multivariable model without selection) could be stated in the “Materials and Methods”

   Reply: The paragraph was relocated tot he „Materials and Methods“ Section

4. In the left column of Tab1e 3, the “UNIVARIABLEE (ALL)” should be corrected as
   “UNIVARIABLE (ALL)” Reply:The mis-spellings were checked and corrected

5. n the Table 2 Baselines after PSM, the “Age” between Surgery only (66.3 +/- 11.9) and CTX + Surgery is still significantly different after PSM. Please further discuss the impact of “Age” in this study in the “Discussion.”

   For the variable “Age” in the Table 1, 2, 3 and 4, the unit “years” for Age is still required

   Reply: This is an important notion. The matching was related not to the absolute numbers but to the age distribution (over/under 70 years) which is why the mean age was unaffected after PSM. Nonetheless, it is important to state that patients in the „surgery only“ group were older in average than those undergoing neoadjuvant chemotherapy which may have biased/influenced overall survival results.

6. n the Page 20, Line 265, there is a redundant full stop/period.

   In the Page 20, Line 267, please check the term “Histoapthologic” or “Histopthologic”.

   Reply: Corrections were done as requested

7. Although the authors noticed the limitations including different treatment strategies in this study, the impact of “adjuvant therapy” on survival of the “primary surgery” group is not clear explained in this manuscript.

   Moreover, there are still some patients receiving primary surgery with advanced disease including T4a, T4b, pN3a, pN3b, and UICC IIIC.

   Most importantly, adjuvant therapy may affect the survival of patients receiving primary surgery with advanced disease as above mentioned.

   Please clarify and discuss whether “adjuvant therapy” is applied to “primary surgery” or not in this retrospective study. If yes, please define the indication of adjuvant therapy after primary surgery.

   Reply: In deed, adjuvant chemotherapy was not applied to patients after primary surgery on a routine basis. This is related to the fact that adjuvant chemotherapy is not a standard of care in the German Gastric Cancer treatment guideline. This is based on the fact, that after surgery there is no detectable target lesion. This clarification was added to the „Materials and Methods“ section.

    

    

Reviewer 3 Report

I read with great interest the work provided by Dimpel et al and even though it is a retrospective study with additional biases, I find the work interesting, and according to my clinical experience, I found it relevant.

I suggest expanding a little the "introduction" section and to further discuss the objective to similar studies provided so far, and also pre-surgery staging imaging techniques for GC. 

Author Response

I suggest expanding a little the "introduction" section and to further discuss the objective to similar studies provided so far, and also pre-surgery staging imaging techniques for GC

Reply:We kindly thank the reviewer fort he positive comments. We expanded the introduction as suggested in the context of previous studies and added a section about pre-surtgery imaging techniques.

Reviewer 4 Report

This study controlled for patient inclusion criteria, used sound data analysis methods, and aimed to detect whether UICC TNM is appropriate for patients treated with multimodality therapy. This study is highly novel. Here, there are some suggestions:

1: Can the results of this paper be further validated by combining some databases?

2: If UICC staging cannot accurately predict the prognosis of a certain group of patients, is there a way to combine other aspects, such as cancer genomics staging, to predict more accurately?

Author Response

1: Can the results of this paper be further validated by combining some databases?

Reply: We kindly thank the reviewer for the postive comments . Certainly, the data have to be furhter validated in combined databases/multicenter analyses, as stated in the final sentence oft he „Conclusion“.

2: If UICC staging cannot accurately predict the prognosis of a certain group of patients, is there a way to combine other aspects, such as cancer genomics staging, to predict more accurately?

Reply: This is a very important notio and requires further evaluation. There is an ongoing debate on how to improve prognostication in gastric cancer patients. The TGCA classification may be an important asset to stratify survival prognosis better. This however, was not included in this analysis. From the authors´point of view it is important to state, that no survival differences were detectable in most of the respective UICC stages due to the fact that neoadjuvant chemotherapy only induces little effect in terms of histopathologic response. This may become better in the near future with FLOT chemotherapy and addition of immuncheckpoint-inhibitors which requires re-evaluation at given time. Momentarily, treatment effects of neoadjuvant chemotherapy may be overstated